Transcranial Magnetic Stimulation (TMS) and Repetitive Transcranial Magnetic Stimulation (rTMS, a variant of TMS in which electromagnetic fields are produced in trains of multiple short pulses) have shown the ability to trigger neuronal firing in selected superficial brain regions. In at least one psychiatric condition (major depression), this effect of TMS and of rTMS appears to constitute an effective therapy. TMS and rTMS instrumentation are currently limited by their inability to focus their magnetic fields at depth. This is chiefly because a magnetic field always diminishes as a function its distance from the source.
Several techniques have been used to deliver stimulation to deep regions of the brain, as will be described. In the use of such technologies, MRI and other imaging techniques are useful for helping to ensure that the stimulation is directed to the correct brain structure. Methods for co-registering internal anatomy with medical instruments, and planning treatment with such medical devices are known in the art, and include methods provided in U.S. Pat. No. 5,207,223 (Adler), U.S. Pat. Nos. 5,891,034 and 6,236,875 (Bucholtz), and by U.S. Pat. Nos. 5,531,227 and 6,351,573 (Schneider). Such registration may be accomplished with the help of commercially available devices designed for surgical navigation, such devices including the Polaris system by Northern Digital (Waterloo, Ontario, Canada).
Magnetic stimulation of the brain and spinal cord has been known since the mid-1980's, Barker A T, Jalinous R, Freeston I L, “Non invasive magnetic stimulation of the human motor cortex” Lancet, 1985; 1:1106-110. A wide variety of clinical applications have been demonstrated, Wassermann, E. M., and S. H. Lisanby, “Therapeutic application of repetitive magnetic stimulation: a review,” Clinical Neurophysiology, 112:1367-1377, 2001, with the major opportunity appearing to be in depression. Martin J L R, Barbanoj M J, Schlaepfer T E, Clots S P V, Kulisevsky J, A G (2002): Transcranial magnetic stimulation for treating depression (Cochrane Review). In (eds.): The Cochrane Library. Oxford: Update Software: The Cochrane Library. Oxford: Update Software.
Several patents and patent applications relate to such areas as electromagnetic coil design, simultaneous monitoring of EEG, simultaneous monitoring with functional MRI, and specific clinical applications. Among these are
U.S. Pat. No, 6,179,771, Mueller, on coil arrangement
U.S. Pat. No. 6,198,958, Ives and Pascual-Leone on monitoring of functional MRI during TMS
U.S. Patent Application 20020007128 and U.S. Pat. No. 6,571,123, Ives and Pascual-Leone on monitoring of the EEG during TMS
U.S. Patent Application 20040078056 and European Patent EP1326681, Zangen et al. on coil design
U.S. Patent Application 2002007125, Davey on coil design
U.S. Pat. No. 6,132,361, Epstein and Davey, coil design and clinical applications. Fox P, Lancaster J. Dodd S. Apparatus and Methods for Delivery of Transcranial Magnetic
Stimulation. United States Patent Application U.S. 2003/0050527 A1 Fox P. Lancaster J. Apparatus and Methods for Delivery of Transcranial Magnetic
Stimulation. United States Patent Application U.S. 2005/0113630 A1 Schneider M B, Mishelevich D J “Robotic Device for Providing Deep, Focused Transcranial Magnetic Stimulation”. United States Patent Application U.S. 20050228209 A1.
While stimulation has shown promise in the treatment of depression, the limitation of the rTMS technique to the stimulation of only superficial structures has been a significant restriction. Depression itself has only been treatable because the superficial structures that are stimulated have neural connections to deep structures where the desirable effects actually occur. One way to increase the magnetic field delivered to depth would be increase the power input to the stimulating electromagnet. Unfortunately, simply increasing the output of the electromagnet is prevented from achieving the desired effect because of the proportional increase at the superficial location, where the field is much stronger to begin with. The resultant magnetic field could easily overwhelm the superficial structures and cause pain, unintended activation of non targeted structures, possibly seizures and neural excitotoxicity.
The general effect of transcranial magnetic stimulation is the depolarization of neural membranes and the resultant production of action potentials. Magnetic fields stimulate neural tissue because electrical current flow is induced. See Davey, K. R., C. H. Cheng, et at (1991). Prediction of magnetically induced electric fields in biologic tissue. IEEE Transactions on Biomedical Engineering 38: 418-422; Davey, K. R., C. M. Epstein, et al. (2004). Modeling the Effects of Electrical Conductivity of the Head on the Induced Electrical Field in the Brain During Magnetic Stimulation. Clinical Neurophysiology 114: 2204-2209.
When the flow of electrical charges in the intracellular and extracellular compartments is interrupted by a neural membrane, a differential voltage is generated across that membrane. The cell membrane is either depolarized or hyperpolarized depending on the direction of the current flow. That direction of the induced electrical-current flow is determined by the directionality of the magnetic field. The embodiments described herein utilize arrays of magnets arranged such that when the coils are simultaneously energized, individual vector components of the applied magnetic field can be, to a functional extent, spatially segregated. By “spatially segregated” it is meant that the arrangement of coils creates regions of enhanced field strength and regions of diminished field strength in the magnetic field in predetermined spatial locations.
Ruohonen, J., “Transcranial Magnetic Stimulation: Modeling and New Techniques” Ph.D. Dissertation in Engineering, Helsinki University of Technology, Espoo, Finland (52 pages), 1998 has presented a potential theoretical model for neural activation by magnetic fields inducing electrical currents. Five cases are described. Case 1: if the induced electrical field is uniform and parallel to the long axis of the axon, no polarization occurs. Case 2: if the magnetic field induces an electrical current with a gradient, the axon membrane has zones of depolarization and hyperpolarization. Case 3: even in the presence of a unithrm field, depolarization will occur at an axon bend. Case 4: transverse activation can produce depolarization and hyperpolarization on opposite sides of the axon. Case 5: depolarization occurs at neural terminations even in the presence of a uniform electrical field. Cases 3 and 5 likely represent the situation with the brain where the axons tend to be thin and curved while Case 4 is representative of the situation in peripheral nerves (e.g., the ulna nerve in the arm) where the nerves tend to be both longer and thicker. TMS is thought to impact axons rather than cell bodies.
There is some evidence that, when applied at rates of approximately one pulse per second or less, recipient nerves are inhibited, or down-regulated in their activity. At rates greater than one pulse per second, the result tends to be excitatory for affected neurons. Stimulating at too great a rate can cause seizures Wassermann, E. M., 1998) “Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, Jun. 5-7, 1996,” Electroencephalography, and Clinical Neurophysiology, 108:1-16, 1998.
Because TMS apparatuses are physically large and bulky, and because their use at effective power levels is generally not comfortable, applying continuous stimulation over a period of hours, days or beyond is not practical. Still, a prolonged therapeutic effect of for example, in the case of depression (Martin et al., 2002) and tinnitus De Ridder D, Verstraeten E, Van der Kelen K, De Mulder G, Sunaert S, Verlooy J, Van de Heyning P, Moller A. Transcranial magnetic stimulation for tinnitus: influence of tinnitus duration on stimulation parameter choice and maximal tinnitus suppression. Otol Neurotol. 2005 July;26(4):616-9 most likely occur because of a re-training of pathways and activity levels.
Factors that influence the strength of neural stimulation depend on many factors including:
(a) Coil configuration—The majority of electromagnets used in clinical treatment are double coils, typically each coil having an outer diameter of 70 mm. The radial component of such an electromagnet is the direction that is geometrically normal (perpendicular) to the plane of the coil face;
(b) Coil size;
(c) Coil material;
(d) Pulse strength;
(e) Pulse shape;
(f) Pulse frequency;
(g) The electrical conductive properties and geometry of each specific area of anatomy receiving magnetic pulses; and
(h) The direction of the nerve or nerve tract receiving the generated electrical field in relation to the direction of the magnetic field at that point. (Ruohonen, 1998; Basser P J, Roth B J. Stimulation of myelinated nerve axon by electromagnetic induction. Med Biol Eng Comput. 29, 261-268. 1998; Fox et al. in U.S. Patent Applications 20050113630 and 20030050527).
Small coils (e.g., 20 to 30 mm in diameter) deliver energy with greater focus than their larger counterparts (Ruohonen, J. and R. J. Ilmoniemi, “Focusing and targeting of magnetic brain stimulation using multiple coils,” Medical & Biological Engineering and Computing, 35:297-301, 1998; Han, B. Y., Chun, I. K., Lee, S. C., and S. Y. Lee, “Multichannel Magnetic Stimulation System Design Considering Mutual Couplings Among the Stimulation IEEE Transactions on Biomedical Engineering, 51:812-817, 2004, and Mueller, U.S. Pat. No. 6,179,771), Unfortunately, the smaller the coil, the less field strength it is able to generate at any given level of electrical input. Increasing the current vastly increases the cooling needs of the magnets. Because of the rapid rate of magnetic field strength fall of with distance from the coil, and the difficulty in providing efficient cooling mean, highly focal coils tend to have little ability to penetrate to depth. For a given magnet, for distances that are small relative to the radius of the magnet's coils, the fall off of magnetic field is a property of the magnet itself. For distances that are large relative to the size of the magnet, the fall-off is one over the distance cubed. This factor limits the ability for the magnetic fields of small coils to penetrate to depth. It should be emphasized that for none of the multi-coil arrays described in the cited literature was delivery to depth an objective, nor would they have been capable of that effect, even with adequate power and cooling, given the obtuse angle of their field confluence, their low power, and melting that uncooled coils of that size and configuration would have undergone at high power delivery. In fact, Ruohonen, et al. state that focusing at depth is not possible, reasoning that the discordance between the location of a magnetic field maxima and an electric field maxima may be displaced (an effect that may be compensated for as described by herein by the inventors), and that the magnetic field entering a head has no radial component (an effect of limited significance if true, and also contested by researchers including Wagner, et al, cited below).
The Hesed coil (Zangen et al., U.S. Patent Application 20040078056 and European Patent EP1326681) was developed in order to more efficiently deliver magnetic field to depth. As a result of its design, the fall-off rate for magnetic field strength over distance is less steep than fbr conventional TMS coils. However this improved depth penetration is achieved with an overall decline in locality when compared with conventional coils. When a magnetic field is applied in the manner described in these references, the intensity of the magnetic field at depth is always less than that at the surface.
The most focal means used today for providing brain stimulation at depth is by use of current-pulsed surgically implanted electrodes, also known as deep-brain stimulation “DBS”. Used for the treatment of conditions such as Parkinson's Disease, DBS also hold promise for the treatment of many neurological and psychiatric disorders, due to its ability to selectively activate and inactivate precise regions of the brain. Unfortunately, DBS necessarily involves an invasive neurosurgical procedure, which is expensive, and fraught with medical risks including intracranial bleeding and infection.
It would be desirable to non-invasively achieve the benefits of DBS by directing electromagnetic energy into deep structures without overwhelming superficial structures. It has been proposed in commentary to simultaneously use multiple coils to summate in deep structures (Sackheim H A. Magnetic Stimulation Therapy and ECT (Commentary). Convulsive Therapy 1994; 10(4); 255-8). Work by Bohning and George (Bohning D E, Pecheny A P, Epstein C M, Speer A M, Vincent D J; Dannels W; George M S Mapping transcranial magnetic stimulation (TMS) fields in vivo with MRI. NeuroReport Volume 8(11), 28 Jul. 1997, p 2535-2538) illustrated the reinforcing effect of simultaneously applied magnetic fields. Two pulsed magnetic fields were delivered at an unspecified acute angle from opposite sides of the temples. The resultant magnetic fields were demonstrated to have a reinfbrcing effect such that the magnetic field demonstrated to be higher at the midline of the brain than it would have had only a single magnet been present. However, this work did not produce or teach a magnetic coil configuration that would enable the intensity at depths to exceed that on the surface, and no further efforts at improving the process were documented.
Fox, et al., (U.S. Patent Applications US 2003/0050527 A1, and U.S. Patent Application US 2005/0113630 A1) propose means for positioning a TMS coil so as to have a maximal biological effect to nerve tissue. This method is based on the use of a single coil targeting a point on the superficial cortex of the brain, and does not discuss the use of multi-coil arrays or concentrating energy at depth.
An alternative approach to non-invasively providing deep brain stimulation using magnetic coils is provided by the inventors of the present invention in Schneider M. B, and D. J. Mishelevich, U.S. Patent Application US 20050228209 A1.
Prior works known by Applicant fall short of configuring coil arrays so as to produce a specific biological effect at a specific locus deep in the brain without significantly impacting superficial structures.
A method for non-invasively modulating the activity of neural tissue at depth at selectable arbitrary locations with the human body, without overwhelming superficial neural structures, would provide significant medical benefits. Additional objects and advantages sought to be achieved by various ones of the methods and systems disclosed herein include:
(a) to provide a system allowing the user to concentrate more magnetic field at depth than at superficial locations that are closer to the stimulating electromagnets, thereby reducing discomfort as well as the risks of seizure and excitotoxicity.
(b) to provide a system that is both non-invasive and more cost effective than implanted Deep Brain Stimulation with electrodes,
(c) to provide a method by which the aim of a neuromodulation device such as that described herein may be offset from the target structure in order to compensate for predicted or observed magnetic/electric field discordance,
(d) to give easy access to a wide variety of neural targets at depth, thereby greatly increasing the breadth of conditions that can be treated such as chronic pain, Alzheimer's Disease, obsessive compulsive disorder, addictions, obesity, Parkinson's Disease and other conditions,
(e) to provide a more effective treatment of depression, which while it can currently be treated with conventional rTMS, could be treated more effectively by direct impact on targets instead of using indirect pathways as is done with prior art methods.